PROJECT SUMMARY/ABSTRACT Concussions are a known risk of contact sports and military operations. Early identification and treatment with a period of rest have become the standard of care. Blood-based brain biomarkers (BBBM) such as S100B, GFAP, and tau, are thought to reflect traumatic axonal injury (AI) and have emerged as an aid to early concussion identification. However, repetitive head hits that do not result in concussion may be the bigger threat to long-term neurologic health. These sub-concussive head hits (SHH) have been linked to an increased risk of long-term cognitive dysfunction, depression, and chronic traumatic encephalopathy (CTE). However, unlike concussions, SHH that result in AI are not routinely identified and thus are not treated with a period of rest without head hits. These AI-producing SHH represent an ignored but potentially treatable threat to long-term neurologic health of athletes involved contact sports, as well as personnel involved in military operations. BBBMs appear ideally suited to detect AI-producing SHH but have not been specifically studied in this regard. The goal of the current proposal is to determine if the BBBM, tau, can detect AI-producing SHHs incurred during a single contact-sporting contest. Our overall goal is to develop BBBMs as a tool for studying the natural history of SHHs and their impact on long-term brain health. To accomplish these goals, we proposed the following Specific Aims: 1. To determine if capillary whole blood tau before and after a single collegiate football game will correlate to SHH 2. To determine if correlation of capillary whole blood tau to SHH will remain significant after controlling for body collisions and aerobic exertion after a single football game 3. To explore a link to traumatic AI by correlating capillary whole blood tau to subject-specific changes in brain white matter on diffusion tensor imaging. At the conclusion of this award we intend to demonstrate that post-game increases in tau are related to SHH, and not to body collisions or aerobic exertion. Correlation of these tau increases to changes in brain WM on diffusion tensor imaging will support the emerging concept that SHH can result in subclinical traumatic AI. Demonstrating that tau can detect AI-producing SHH would allow it to be employed as a unique tool for bridging our understanding of how repetitive head hits may result in short- and long-term neurologic sequelae, and as a biomarker for therapeutic studies aimed at mitigating these sequelae. Our results will also advance broader TBI research efforts aimed at interpreting increases in BBBM immediately after a single head hit or blast exposure occurring in the setting of aerobic exertion or body collisions.